Proapoptotic Bcl-2 inhibitor as host directed therapy for pulmonary tuberculosis

Abstract

Mycobacterium tuberculosis establishes within host cells by inducing anti-apoptotic Bcl-2 family proteins, triggering necrosis, inflammation, and fibrosis. Here, we demonstrate that navitoclax, an orally bioavailable, small-molecule Bcl-2 inhibitor, significantly improves pulmonary tuberculosis (TB) treatments as a host-directed therapy. Addition of navitoclax to standard TB treatments at human equipotent dosing in mouse models of TB, inhibits Bcl-2 expression, leading to improved bacterial clearance, reduced tissue damage / fibrosis and decreased extrapulmonary bacterial dissemination. Using immunohistochemistry and flow cytometry, we show that navitoclax induces apoptosis in several immune cells, including CD68 + and CD11b + cells. Finally, positron emission tomography (PET) in live animals using novel, clinically translatable biomarkers for apoptosis (¹⁸F-ICMT-11) and fibrosis (¹⁸F-FAPI-74) demonstrates that navitoclax significantly increases apoptosis and reduces fibrosis in pulmonary tissues, which are confirmed using post-mortem studies. Our studies suggest that proapoptotic drugs such as navitoclax can improve pulmonary TB treatments, and should be evaluated in clinical trials.